Nourianz (istradefylline) / Kyowa Kirin - LARVOL DELTA

Intraperitoneal Administration of Adenosine A2A Receptor Antagonist Reduces Neuroinflammatory and Antioxidant Responses in GM2 Gangliosidosis Mouse Model. (PubMed, Neuropharmacology) - "Overall, istradefylline attenuated selected neuroinflammatory and glial alterations and modulated antioxidant-response markers in Hexa-/-Neu3-/- mice. These findings support further investigation of A2A receptor antagonism as an adjunctive symptomatic and anti-inflammatory strategy, potentially in combination with treatments that directly target the underlying enzymatic deficiency."

Journal • Preclinical • CNS Disorders • Genetic Disorders • Inflammation • Lysosomal Storage Diseases • Metabolic Disorders • Mood Disorders • Psychiatry • Rare Diseases • Solid Tumor • ADORA2A • CAT • CCL2 • CCL3 • CXCL10 • GFAP • IL1B • SOD2

Enhancing Rehabilitation in Aging Study (ERAS) (clinicaltrials.gov) - P1/2 | N=38 | Not yet recruiting | Sponsor: University of Florida

New P1/2 trial

Electronic structure-activity relationships of adenine-based istradefylline derivatives investigated by DFT, topological analysis, and exploratory neuronal excitability modeling. (PubMed, Sci Rep) - "Furthermore, an exploratory descriptor-based multi-scale modeling approach is proposed to conceptually map global and local electronic properties-chemical softness, polarizability, dipole moment, and electrostatic potential-onto simulated neuronal excitability; this mapping should be interpreted as a conceptual framework rather than a demonstration of biological or pharmacological activity. These findings suggest the potential importance of a balanced interplay between global and local electronic properties in understanding activity-related trends in A2AR antagonists, while acknowledging that the present computational results require further experimental and receptor-level validation."

Journal • CNS Disorders • ADORA2A

Cannabinoid and adenosine A2A receptor crosstalk regulates postnatal and adult hippocampal neurogenesis. (PubMed, Br J Pharmacol) - "Taken together, these findings suggest a crosstalk between the adenosinergic and cannabinergic systems responsible for regulating hippocampal progenitor dynamics. The identification of CB1-A2A receptor heteromerization provides new insights into the molecular basis of neurogenic modulation and highlights a promising avenue for the development of novel proneurogenic therapeutic strategies."

Journal • ADORA2A

Early neural shift detection using functional magnetic resonance imaging: a pilot study with Parkinson's disease patients undergoing istradefylline and hybrid assistive limb interventions. (PubMed, Front Neurol) - "Short-term istradefylline administration elicited measurable changes in brain activation patterns without corresponding clinical or cognitive gains, which suggests that fMRI may serve as a more sensitive biomarker of early, subthreshold neural adaptations than conventional assessments. However, these findings must be interpreted with caution due to the small sample size and exploratory nature of the study."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease • ADORA2A

Targeting oncomucin-driven immunosuppression improves the efficacy of K-rasG12D inhibition in pancreatic cancer. (PubMed, Gastroenterology) - "Transmembrane oncoMUCs promote immune evasion in PDA through EGFR/UNC5B signaling, and their targeting enhances the efficacy of K-rasG12D inhibition, suggesting oncoMUCs as novel immune regulators and therapeutic targets in PDA."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • HAVCR2 • KRAS • MUC16 • MUC4 • MUC5AC • VSIR

The Adenosine A2A Receptor Antagonist KW6002 Mitigates Aldosterone-induced Central Serous Chorioretinopathy in Mice. (PubMed, Neuropharmacology) - "Our findings show that the A2AR antagonist KW6002 or A2AR-KO offers a protective effect in experimental CSC, reduces inflammation, and maintains the integrity of the BRB, which may be associated with the inhibition of the TNF-α/NF-κB-MMP-2/9 pathway. These findings present a new method for preventing and treating CSC, which will guide our future clinical strategy development."

Journal • Preclinical • Inflammation • Retinal Disorders • ADORA2A • CLDN1 • CLDN5 • IL1B • IL6 • MMP2 • MMP9 • TJP1 • TNFA

Current status of patients participating in the domestic clinical trial of Istradefylline (JSNE 2026) - No abstract available

Clinical • CNS Disorders • Gene Therapies • Movement Disorders • Parkinson's Disease

Purinergic modulation in Parkinson's disease: the dual role of istradefylline in motor and cognitive outcomes. (PubMed, Purinergic Signal) - "Understanding the molecular mechanisms behind these opposing effects is essential for optimizing its use and minimizing neurocognitive risks in PD patients. Future longitudinal trials are vital to clarify its long-term safety profile and disease-modifying potential."

Journal • Review • CNS Disorders • Inflammation • Metabolic Disorders • Movement Disorders • Parkinson's Disease

Dual CD73/A2AR blockade modulates the neurotoxic astrocyte phenotype without disrupting core inflammatory signaling. (PubMed, Front Pharmacol) - "Concomitant pharmacological inhibition of CD73 (APCP, 100 μM) and A2AR (istradefylline, 10 μM) was applied...These findings demonstrate that dual CD73/A2AR blockade selectively reconfigures astrocyte inflammatory networks under the tested conditions, without broadly suppressing inflammatory or homeostatic functions at the examined time point. This supports the CD73/A2AR axis as a promising therapeutic target for limiting chronic astrocyte-driven neurotoxicity."

Journal • Inflammation • ADORA2A • CD73 • IL1B • IL6 • NOS2 • NT5E • TNFA • VCAM1

Adenosine A2A Receptors Control the Mis-Localization of Aquaporin-4 in Rats Subject to Repeated Restraint Stress. (PubMed, J Neurochem) - "KW-6002 treatment also prevented the RRS-induced decrease of AQP4 density in gliosomes, corresponding to astrocytic membrane endfeet, the perivascular AQP4 polarization in astrocytes, and both perivascular and cellular AQP4 coverage. These findings show that A2AR controls AQP4 polarization upon restraint stress and prompt considering that A2AR might control the impact of repeated stress on brain dysfunction through a control of the glymphatic system."

Journal • Preclinical • Mood Disorders • Psychiatry • ADORA2A

Adenosine A2A receptors in the chorioid plexus are causal in mediating the development of hydrocephalus. (PubMed, Purinergic Signal) - "The A2AR-SPAK (SPS1-related proline/alanine-rich kinase)-PI3K (phosphoinositide 3 kinase)-Akt (protein kinase B)-NF-κB (a nuclear factor)-ATP1A2 (a Na+,K+-ATPase) pathway was suggested to be instrumental in hydrocephalus development. The clinically important conclusion deriving from this observation was that A2AR blockade by istradefylline, a Food and Drug Administration-approved drug could be introduced into the therapy of human hydrocephalus."

Journal • Review • CNS Disorders • Hematological Disorders • Infectious Disease • Oncology • Ventriculomegaly • ADORA2A

Contribution of adenosine A2A receptor agonist and antagonist on ovarian ischemia/reperfusion injury in rats. (PubMed, Turk J Med Sci) - "To determine the effects of an A2A receptor agonist regadenoson, an A2A receptor antagonist istradefylline, and istradefylline nanosuspension on ovarian ischemia/reperfusion (I/R) injury in rats. Serum disulfide levels were increased in the I/R group, and this increase was suppressed by regadenoson. These data showed that adenosine A2A receptors may contribute to the ovarian I/R injury and regadenoson can produce protective effects."

Journal • Preclinical • Cardiovascular • Reperfusion Injury • ADORA2A

Human Neuraminidase 3 reduces the severity of Tay-Sachs disease symptoms in a mouse model. (PubMed, Neurochem Int) - "Rotarod and footprint analyses showed improvements at 20 weeks. Our results provide the first in vivo evidence that AAV-mediated human Neu3 expression and Istradefylline may slow disease progression, reduce neuropathology, and lessen motor deficits in the Hexa-/-Neu3-/- mouse model of TSD."

Journal • Preclinical • Ataxia • CNS Disorders • Gene Therapies • Genetic Disorders • Metabolic Disorders • Movement Disorders • LAMP1

High-throughput screening for the discovery of antidepressants targeting adenosine A2A receptors. (PubMed, Bioorg Chem) - "Remarkably, these compounds exhibited rapid-onset antidepressant effects within 1 h, without obvious abnormal behaviors or mortality, and their efficacy was comparable to the A2AR antagonist istradefylline (KW6002). In summary, we have established a robust HTS method for the efficient discovery of A2AR-targeting compounds. This work has led to the identification of novel antagonist compounds with rapid-acting antidepressant-like potential, thereby providing a solid foundation for the development of new antidepressant therapeutics."

Journal • CNS Disorders • Depression • Psychiatry • ADORA2A

Expanding Clinical Experience With Istradefylline in ADCY5-Related Movement Disorder: A Case With No Benefit. (PubMed, Mov Disord Clin Pract) - No abstract available

Journal • Movement Disorders

Intrathecal delivery of AAVrh10-mHexa combined with anti-inflammatory treatment reduces neuropathological markers and extends the lifespan of mice with early-onset Tay-Sachs disease. (PubMed, Metab Brain Dis) - "Correspondingly, their motor activity also improved. These results suggest that AAVrh10-based intrathecal delivery combined with istradefylline provides a promising therapeutic strategy for treating Tay-Sachs disease."

Journal • Preclinical • Gene Therapies • Genetic Disorders • Inflammation • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Solid Tumor • CCL2 • CCL3 • LAMP1

Adenosine 2A Receptor Antagonism and AIH in ALS (clinicaltrials.gov) - P1/2 | N=40 | Active, not recruiting | Sponsor: University of Florida | Recruiting ➔ Active, not recruiting | Trial completion date: May 2026 ➔ Aug 2026

Enrollment closed • Trial completion date

Adenosine A₂A receptor as a dual-acting molecular switch: Glial morphological changes and neurovascular tissue remodeling in neuroinflammation and neurodegeneration. (PubMed, Tissue Cell) - "A₂AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data...The dual regulatory role of A₂AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A₂AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Movement Disorders • Multiple Sclerosis • Parkinson's Disease • IL10

Long-term outcomes associated with istradefylline versus catechol-O-methyltransferase inhibitors in patients with Parkinson's disease: a nationwide real-world cohort study. (PubMed, Parkinsonism Relat Disord) - "Istradefylline was associated with reduced mortality and treatment escalation but increased fracture risk compared with COMT inhibitors, supporting further evaluation of adenosine A2A antagonists."

Journal • Real-world evidence • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dementia • Depression • Infectious Disease • Movement Disorders • Musculoskeletal Diseases • Orthopedics • Parkinson's Disease • Pneumonia • Psychiatry • Respiratory Diseases • ADORA2A • COMT

Involvement of Adenosine A2A Receptors in Anxiety-Like Behaviors in Tetrahydrocannabinol-Treated Mice. (PubMed, Brain Behav) - "These findings contribute to the understanding of THC's complex pharmacological actions, highlighting the importance of receptor cross talk in modulating anxiety and other behavioral outcomes."

Journal • Preclinical • Mood Disorders • Psychiatry • ADORA2A

Inhibition of Retinal AdoRA2a Activity Attenuates Myopia Progression. (PubMed, Invest Ophthalmol Vis Sci) - "Our results demonstrate that retinal AdoRA2a plays a pivotal role in myopia progression. Our findings identify the retina as the critical site for AdoRA2a's action and suggest an underlying AdoRA2a-Drd2 interaction mechanism, revealing the possible therapeutic potential of KW6002 in myopia progression."

Journal • Ophthalmology • ADORA2A • CD73 • DRD2 • ENTPD1 • NT5E

The persisting puzzle of OFF time in advanced Parkinson's disease. (PubMed, Brain) - "The complexity of managing motor fluctuations is further highlighted by the effectiveness of various non-dopaminergic adjunctive therapies for reducing OFF time in levodopa-treated patients, as shown by placebo-controlled clinical trials with adjunctive istradefylline, amantadine, zonisamide, and deep brain stimulation. For achieving better control of OFF time in advanced Parkinson's disease, there is a need for discovering therapeutic strategies acting beyond the limits of today's dopaminergic therapies. Modeling brain circuitry with tools like deterministic neural-computational analysis may provide valuable pharmacological and electrophysiological insights for better understanding of motor fluctuations and the choice of appropriate therapeutic targets."

Clinical • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Selective antagonism of adenosine A2A receptor reduces hypobaric hypoxia-induced neuroinflammation by inhibiting cGAS-STING pathway. (PubMed, Sci Rep) - "Less cytosolic mtDNA accumulation after KW6002 treatment attenuated HY-induced activation of cGAS-STING inflammatory signaling pathway. ADORA2A activation mediates HY cognitive impairment, which is achieved by activating EPAC1 and VDAC1 to mediate mtDNA release and cGAS-STING signaling pathway to drive neuroinflammation cascade."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • ADORA2A • ADORA2B • VDAC1

Caffeine Mitigates Adenosine-Mediated Angiogenic Properties of Choroidal Endothelial Cells Through Antagonism of A1 Adenosine Receptor and PI3K-AKT Axis. (PubMed, Cells) - "We recently showed that systemic caffeine administration suppressed CNV in vivo, an effect partly reproduced by the adenosine receptor A2A antagonist Istradefylline. Here, we investigated the cell-autonomous effects of caffeine on mouse choroidal endothelial cells, focusing on its role as an adenosine receptor antagonist and its potential to inhibit pathological neovascularization."

Journal • Age-related Macular Degeneration • CNS Disorders • Dry Age-related Macular Degeneration • Inflammation • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration